Covariate effect on constancy assumption in noninferiority clinical trials.

Noninferiority (NI) clinical trials are getting a lot of attention of late due to their direct application in biosimilar studies. Because of the missing placebo arm, NI is an indirect approach to demonstrate efficacy of a test treatment. One of the key assumptions in the NI test is the constancy assumption, that is, that the effect of the reference treatment is the same in current NI trials as in historical superiority trials. However, if a covariate interacts with the treatment arms, then changes in distribution of this covariate will likely result in violation of constancy assumption. In this article, we propose four new NI methods and compare them with two existing methods to evaluate the change of background constancy assumption on the performance of these six methods. To achieve this goal, we study the impact of three elements-(1) strength of covariate, (2) degree of interaction between covariate and treatment, and (3) differences in distribution of the covariate between historical and current trials-on both the type I error rate and power using three different measures of association: difference, log relative risk, and log odds ratio. Based on this research, we recommend using a modified covariate-adjustment fixed margin method.